rs60194757

Variant names:

• chr12-1908041-G-A
• rs60194757
• NM_172364.5:c.487-4C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-1908041-G-A
• chr12-1908041-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172364.5(CACNA2D4):​c.487-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,607,862 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (22 hom.)
• Consequence: CACNA2D4 NM_172364.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007083
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.306
• Publications: 2 publications found

Genes affected

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

CACNA2D4 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-1908041-G-A is Benign according to our data. Variant chr12-1908041-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00998 (1521/152334) while in subpopulation AFR AF = 0.0336 (1396/41582). AF 95% confidence interval is 0.0321. There are 29 homozygotes in GnomAd4. There are 695 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.487-4C>T		splice_region intron	N/A	NP_758952.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.487-4C>T		splice_region intron	N/A	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.487-4C>T		splice_region intron	N/A	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.487-4C>T		splice_region intron	N/A	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.00997 AC: 1518 AN: 152216 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00269 AC: 662 AN: 245888 AF XY: 0.00216

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00128 AC: 1856 AN: 1455528 Hom.: 22 Cov.: 33 AF XY: 0.00118 AC XY: 854 AN XY: 722936

African (AFR) AF: 0.0334 AC: 1117 AN: 33400

American (AMR) AF: 0.00315 AC: 140 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39572

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85704

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53214

Middle Eastern (MID) AF: 0.00576 AC: 33 AN: 5734

European-Non Finnish (NFE) AF: 0.000337 AC: 373 AN: 1107478

Other (OTH) AF: 0.00311 AC: 187 AN: 60084

GnomAD4 genome AF: 0.00998 AC: 1521 AN: 152334 Hom.: 29 Cov.: 33 AF XY: 0.00933 AC XY: 695 AN XY: 74490

African (AFR) AF: 0.0336 AC: 1396 AN: 41582

American (AMR) AF: 0.00536 AC: 82 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68034

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00565 Hom.: 3

Bravo AF: 0.0111

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Retinal cone dystrophy 4 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.94
PhyloP100		0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60194757; hg19: chr12-2017207;